Aberrations In Blood Lymphocytes Research Articles

Cytogenetic Violations in Blood Lymphocytes of Macaca Mulatta Monkeys in the Long Term after Irradiation with Accelerated Krypton Ions

A study has been performed of cytogenetic violations that occur in blood lymphocytes of Macaca mulatta monkeys after local exposure of the hippocampal region to accelerated 78Kr ions at a dose of 3 Gy. Analysis revealed a low level of chromosomal aberrations in the control group of monkeys. The number of cells with chromosomal aberrations did not exceed 1.67٪. The main fraction was chromatid-type aberrations. A cytogenetic analysis of peripheral blood lymphocytes of monkeys exposed to accelerated krypton ions revealed the maximum level of chromosomal aberrations 24 h after exposure, which exceeded the control level by 2.7 times. By day 96, the number of aberrations decreased 1.7-fold. However, it still exceeded the control level. By 460 days, some animals showed a slight increase in the number of aberrations compared to the previous observation period. In the long term, a number of irradiated animals showed deviations from the standard behavior of monkeys. Data on chromosomal aberrations in blood lymphocytes of monkeys and humans after in vitro irradiation with 170 MeV protons are compared. The relevance of this research is due to the preparation of interplanetary manned flights.

Cytogenetic validation of DS02R1-estimated dose for atomic bomb survivors in Hiroshima and Nagasaki with FISH

Introduction For Hiroshima and Nagasaki survivors, it has not been possible to calculate individual doses from the cytogenetic data and compare them with the physically estimated doses. This is because the cytogenetic studies used solid Giemsa staining which only provides the percent of cells bearing at least one stable-type aberration (most of the unstable-type aberrations had already disappeared), and a gamma-ray dose plus a 10-times neutron dose was used to integrate the data for both cities. Objectives To compare the FISH-derived gamma-ray dose with the DS02R1-derived gamma-ray dose after correcting for a contribution of the neutron dose. It was also an attempt to determine if the frequency of stable-type aberrations had remained unchanged after the exposure. Methods Stable exchange-type aberration data was obtained using the 2-color FISH method from 1,868 atomic bomb survivors in Hiroshima and Nagasaki. The collected frequency was first extended to a genome-equivalent frequency. Then, by using known induction rates of exchange-type aberrations in vitro caused by neutrons and gamma-rays, respectively, and the mean relationship between the neutron and gamma-ray doses in the DS02R1 estimates for the survivors, the gamma-ray effect was estimated from the total yield of translocations. Results It was found that over 95% of individual cytogenetic gamma-ray doses fell within the expected range of plus/minus about 1 Gy from the DS02R1 dose and the mean slope for the linear regression was 0.98, which reassures us of the validity of the DS02R1 study. Conclusions The present results demonstrate the validity of the individual DS02R1 doses, and that the frequency of stable-type aberrations in blood lymphocytes did not decay over the years, and thus is useful for retrospective dose evaluations of exposures which took place in the distant past.

Cytogenetic features in adolescent girls with abnormal uterine bleeding which is comorbid with multi­factor diseases

Objective — to study the state of chromosomal apparatus in adolescent girls with abnormal uterine bleeding which is comorbid with multi-­factor diseases.
 Materials and methods. Cytogenetic analysis has been carried out in 25 girls aged 14 to 17 with abnormal uterine bleeding (AUB) which is comorbid with multifactor diseases (endocrine and nervous). The comparison group included 25 age-matching healthy girls. All the girls have been examined in the Laboratory of Medical Genetics of the Institute. Statistical processing of the study results has been carried out following the Student’s t­test with the use of Excel software package.
 Results and discussion. According to the data of cytogenetic analysis, it has been established that the total level of chromosome aberrations in blood lymphocytes of sick girls constituted 5.44 % and exceeded this value by a factor of 2.2 in comparison with the frequency in healthy girls. A 1.8-­fold increase of the number of chromosome aberrations was observed; among them the paired acentric fragments have been recorded twice as often. Chromatid­type aberrations in blood lymphocytes were observed in 2.9 times oftener in girls with AUB, mainly due to an increase in the number of single acentric fragments. The frequency of genomic disorders was 0.60 % that is five times more than their frequency in blood lymphocytes of healthy girls.
 Conclusions. Cytogenetic analysis conducted in adolescent girls with abnormal uterine bleeding and comorbid pathology have revealed an increase of the overall level of chromosome aberrations in comparison with healthy girls. Paired acentric fragments prevailed among chromosome aberrations, single acentric fragments prevailed among chromatid-­type aberrations, polyploid cells prevailed among genomic disorders.

Анализ аберраций числа копий ДНК в лимфоцитах крови работников атомной отрасли, подвергшихся внешнему радиационному воздействию

Введение. Поиск биологических маркёров индивидуальной радиочувствительности человека остаётся чрезвычайно актуальной проблемой современной радиационной медицины. Цель - провести оценку аберраций числа копий ДНК (copy number aberration - CNA) в лимфоцитах крови работников, подвергшихся хроническому профессиональному радиационному воздействию. Методы. Обследовано 20 условно здоровых работников Сибирского химического комбината, подвергшихся внешнему радиационному воздействию. Всем обследованным лицам провели стандартный цитогенетический анализ. Выделенная ДНК из образцов крови исследована с использованием микроматрицы «CytoScan HD Array» («Affymetrix», США). Для обработки результатов микрочипирования использовали программу «Chromosome Analysis Suite 4.3» («Affymetrix», США). Результаты. У 4 из 20 работников обнаружено 4 CNA различных типов: 3 мозаичные амплификации, 1 мозаичная делеция. Заключение. Обнаруженные 4 CNA, кандидата на происхождение de novo, не индуцированы хроническим низкоинтенсивным облучением, так как не показали ассоциацию с ним. В данном исследовании, предположение о связи возникших de novo CNA с радиочувствительностью индивидов не подтвердилось. Необходимы дальнейшие исследования механизмов сохранения хромосомных аберраций с целью обнаружения маркёров индивидуальной радиочувствительности. Introduction. The search for biological markers of individual radiosensitivity remains an extremely urgent problem of modern medicine. Aim: to evaluate of the copy number aberrations in the blood lymphocytes of workers exposed to occupational radiation exposure. Methods. The object of the study was the blood of 20 relatively healthy workers of the Siberian Chemical Combine, exposed to external radiation. A standard cytogenetic analysis was performed for all the examined individuals. The blood DNA was examined using a «CytoScan HD Array» microarray («Affymetrix», USA). To process the results of microchipping, a program was used «Chromosome Analysis Suite 4.3» («Affymetrix», США). Results. For4 workers found out 4 CNA: 3 mosaic amplifications, 1 mosaic deletion. Conclusion. The detected 4 candidates for the origin of de novo CNA were not induced by chronic low-intensity radiation, as they did not show an association with radiation. In this study, the assumption about the connection of de novo CNA with the radiosensitivity of individuals was not confirmed. Further studies of the mechanisms of XA preservation are needed in order to detect markers of individual radiosensitivity.

Chromosomal Aberrations in Blood Lymphocytes as Predictors of Respiratory Function After Stereotactic Lung Irradiation.

Due to the profound difference in radiosensitivity of patients and various side effects caused by this phenomenon, a radiosensitivity marker is needed. Prediction by a marker may help personalise the treatment. In this study, we tested chromosomal aberrations (CA) of in vitro irradiated blood as predictor of pulmonary function decrease of nonsmall cell lung cancer (NSCLC) patients and also compared it with the CAs in the blood of irradiated patients. Peripheral blood samples were taken from 45 lung cancer patients before stereotactic radiotherapy (SBRT) and immediately after the last fraction and 3, 6, 9, 12, 15, 18, 21, and 24 months later. Respiratory function measurements were performed at the same time. Diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1s), and FEV1s/FVC (FEV1%) were monitored. Metaphase preparations of lymphocytes were made with standard procedures, and chromosome aberrations were analysed. In our cohort, the 36-month local relapse-free survival was 97.4%, and the distant metastasis-free survival was 71.5% at 36 months. There was no change in the mean of the pulmonary function tests (PFTs) after the therapy. However, there was a considerable variability between the patients. Therefore, we subtracted the baseline and normalised the PFT values. There were significant decreases at 12–24 months in relative FEV1s and relative FEV1%. The tendentious decrease of the PFTs could be predicted by the in vitro chromosome aberration data. We also found connections between the in vitro and in vivo CA values (i.e., dicentrics plus rings after 3 Gy irradiation predicts dicentric-plus-ring value directly after the radiotherapy/V54 Gy (p = 0.001 24.2%)).We found that—after further validation—chromosome aberrations resulted from in vitro irradiation before radiotherapy can be a predictive marker of pulmonary function decrease after lung irradiation.

Taxonomic diversity of sputum microbiome in lung cancer patients and its relationship with chromosomal aberrations in blood lymphocytes

Here we report a pilot-sized study to compare the taxonomic composition of sputum microbiome in 17 newly-diagnosed lung cancer (LC) patients and 17 controls. Another object was to compare the representation of individual bacterial genera and species in sputum with the frequency of chromosomal aberrations in the blood lymphocytes of LC patients and in controls. Both groups were male; average age 56.1 ± 11.5 in patients and 55.7 ± 4.1 in controls. Differences in the species composition of bacterial communities in LC patients and controls were significant (pseudo-F = 1.94; p = 0.005). Increased prevalence in LC patients was detected for the genera Haemophilus and Bergeyella; whereas a decrease was observed for the genera Atopobium, Stomatobaculum, Treponema and Porphyromonas. Donors with high frequencies of chromosomal aberrations had a significant reduction in the microbiome of representatives of the genus Atopobium in the microbiome and a simultaneous increase in representatives of the species Alloprevotella compared to donors with a low level of chromosomal aberrations in lymphocytes. Thus, a comparison of the bacterial composition in the sputum of donors with cytogenetic damages in theirs lymphocytes, warrants further investigations on the potential role of microorganisms in the process of mutagenesis in somatic cells of the host body.

Polymorphisms of genes of DNA repair enzymes and indicators of genome instability in coal mine workers

Introduction. Coal industry is one of the main economy sectors of many countries. However, it poses a danger to the environment and human health. Since the Kemerovo region is a region with a developed industry, the problem of maintaining genetic homeostasis is highly relevant. Miners are exposed to various harmful factors that can act as genotoxicants and cause various DNA damage.The aim of the study was to explore the associations of polymorphic variants of DNA repair genes with chromosomal instability in coal mining workers.Materials and methods. Polymorphic variants of genes of enzymes of reparation DNA (XPD (rs13181), XPG (rs17655), XRCC2 (rs3218536), XRCC3 (rs861536), XRCC4 (rs2075685), XRCC4 (rs1805377)) and chromosomal aberrations in blood lymphocytes of 307 miners of coal mines in Kuzbass, 338 residents of the Kemerovo region who did not work in industrial enterprises were analyzed.Results. The frequency of chromosomal aberrations in the group of miners (4.01±0.14) was significantly higher than in the group of individuals who did not work in production (1.67±0.06, p<0.0000005). We found that allelic variants in genes XPD (rs13181), XRCC3 (rs861536), XRCC4 (rs2075685), are associated with the increased chromosomal damage in miners.Conclusions. Coal production has a negative impact on the genome of workers and can lead to the formation of cytogenetic disorders, which determines the need to develop measures for the comprehensive prevention of diseases caused by the accumulation of DNA damage. The results of the study will expand the existing understanding of the formation of the human genetic apparatus individual sensitivity to the effects of genotoxic factors, as well as formulate recommendations for coal mining workers in accordance with their genetic characteristics.Conflict of interests. The authors declare no conflict of interests.

Estimation of chromosome disorders in workers at coal thermal power plant

Introduction. Coal heat power stations are characterized by severe hazardous eff ect of occupational environment on workers. Objective. To analyze chromosomal disorders in workers of thermal power plant working on coal from Kuznetsk coal fi eld (West Siberia). Materials and methods. Th e authors studied level and specter of chromosomal aberrations in blood lymphocytes of 185 workers of Kemerovo thermal power plant and 218 inhabitants of the same location, not working on industrial enterprises (Kemerovo, Russia). For every individual, average number of 200 metaphase plates of high quality was analyzed. Results. Findings are that the workers of thermal power plant have levels of chromosomal aberrations signifi cantly higher than those of reference group (3,01±0,13% vs. 1,45±0,08%; р<0,00001). With that, increased frequency is seen both for chromatid aberrations and for chromosomal ones — that indicates complex exposure to chemical and radiation factors. Conclusions. Th e results obtained necessitate elaboration of measures to decrease genotoxic hazards in the occupational environment.

Оценка последствий дистанционной лучевой терапии у больных раком лёгкого путём анализа хромосомных аберраций в лимфоцитах крови

Оценка последствий дистанционной лучевой терапии у больных раком лёгкого путём анализа хромосомных аберраций в лимфоцитах крови

Platelets, lymphocytes and erythrocytes from Alzheimer's disease patients: the quest for blood cell-based biomarkers.

In elderly population, Alzheimer's disease is a common neurodegenerative disorder and accounts for about 70% of all cases of dementia. The neurodegenerative processes of this disease start presumably 20 years ahead of the clinical beginning of the disorder. The postmortem histopathological examination, brains from Alzheimer's disease patients with characteristic features like amyloid plaques and neurofibrillary tangles, neuronal and synaptic disintegration confirm the final diagnosis of Alzheimer's disease. Senile plaques are composed of -amyloid peptide, deriving from the amyloid protein precursor, which is present not only in the brain tissue, but also in other non-neuronal tissues. Some investigations reported that platelets possess amyloid protein precursor and all the enzymatic activities required for the metabolism of this protein throughout the same pathways present in the brain. Thus, platelets may be a good peripheral blood cell-based biomarker to study the onset of Alzheimer's disease. Another line of research indicated molecular and cellular aberrations in blood lymphocytes and erythrocytes from Alzheimer's disease patients and emphasizes the systemic nature of the disease. In this review, we will summarize the recent knowledge on the involvement and/or response of platelets, lymphocytes and red blood cells in the circulation during Alzheimer's disease development. The facts will be reviewed with the special possibility for applying the above blood cells as Alzheimer's disease preclinical and antemortem blood cell-based biomarkers.

Strong associations between chromosomal aberrations in blood lymphocytes and the risk of urothelial and squamous cell carcinoma of the bladder

Chromosomal aberrations (CAs) in blood lymphocytes have been shown to be associated with overall cancer risk and aging. However, their relationship to bladder cancer risk remains to be elucidated. In a case-control study of bladder cancer in Egypt, we examined the relationship between the increased frequency of CAs in blood lymphocytes and bladder cancer risk. High frequency of CAs was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 3.90, 95% confidence interval (CI) = 2.65–5.73]. The associations were somewhat stronger in squamous cell carcinomas (SCC, OR = 4.90) than in urothelial carcinomas (UC, OR = 3.62). We also identified chromosome specific CAs for chromosomes 3, 4, 5, 8, 9, 10, 11, 12, 17, 19 that were significantly associated with an increased risk of bladder cancer. We observed particularly strong associations between aberrations of chromosomes 12, 13, 17 and risk of SCC (OR = 7.06, 6.91 and 6.23, respectively). Conclusion: increased frequency of chromosomal aberrations in blood lymphocytes was significantly associated with bladder cancer risk. Overall and chromosome specific aberrations in blood lymphocytes may be a unique set of biomarkers for risk assessments of SCC and UC.

THE QUANTITY OF CELLS NECESSARY FOR THE ANALYSIS OF CHROMOSOMAL ABERRATIONS AT RESIDENTS OF KUZBASS PATIENTS WITH CANCER OF LUNG

The pilot research executed in 2014 in selection of patients with lung cancer (LC) and healthy residents of Kemerovo region (338 Caucasians: 159 having LC and 179 healthy) has shown statistically significant distinction between groups of level and range of chromosome aberrations in blood lymphocytes. Patients of cancer detection centre (before treatment) had increased chromosome aberration values, both of chromatid and chromosomal types. 250 metaphases were analyzed for each individual. For accuracy test of the received quantitative characteristics of mutational process and definition required and enough number of cells necessary for the analysis, at essential increase in further selection volume, 50 LC patients (selected randomly), comparison of cytogenetic data has been carried out in the analysis of 200 cells, then 400, 600, 800, 1000 and over 1000 metaphases. Totally, in this subgroup 50 000 cells which were at a mitosis metaphase stage have been studied. Statistical data processing was carried out with the use of a software package for Windows Statistica 8.0. Using Mann-Whitney U-criterion it is confirmed that frequency of aberrant metaphases doesn't change significantly for statistics in case of increase in analyzed cells quantity; the analysis of 200 cells gives no less reliable information about the individual CA level, than the analysis of 1000 and more cells. In this regard it is possible to make the conclusion that 200 cells is necessary and enough number of analysed metaphases at the assessment of individual level and chromosomal aberrations' range for Kemerovo region residents who have lung cancer.

Realizing the European Network of Biodosimetry (RENEB) – concluding remarks

Just over half a century has elapsed since dicentric aberrations in blood lymphocytes were first used at Oak Ridge to investigate a few accidental overexposures to ionising radiation. The scientifi...

Abstract 4157: Autosome instability and loss of chromosome Y in blood lymphocytes predict lung cancer risk

Abstract Background: Cancer cells are characterized by frequent chromosome aberrations (CA), which reflect defects of the underlying mechanisms that maintain genomic stability. Chromosome aberrations in peripheral blood lymphocytes has been shown to be associated with overall cancer risk in previous small studies. However, the relationship between types of chromosome aberrations in blood lymphocytes and lung cancer risk has not been well defined. In a case-control study of non-small cell lung cancer, we evaluated if CA in autosomes and sex chromosomes were predictive of lung cancer risk. Method: Chromosome aberrations were determined by G-banding analysis of metaphase chromosomes from short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between CAs and lung cancer risk. Results: Autosome instability (defined as CA in any of the 22 pairs of autosomes in > 5% of the cells) was significantly associated with lung cancer risk among individuals who were <= 67 years of age; adjusted odds ratio (OR) of 5.0 [95% confidence interval (CI) = 1.6 - 15.3]. There was no significant association between autosome instability and lung cancer risk in individuals who were older than 67 years of age. Loss of chromosome Y was significantly associated with an elevated risk of lung cancer among males; adjusted OR of 3.2 (95% CI = 1.2 - 8.8). This association appeared to be stronger in older males (> 67 years of age) and in African American males. We observed no significant association between loss of chromosome X and lung cancer risk in both males and females. Conclusion: Autosome instability and loss of chromosome Y in blood lymphocytes were significantly associated with lung cancer risk. Analysis of chromosome aberrations in blood lymphocytes may be a promising tool for the identification of sub-population who are at high risk of developing lung cancer. Citation Format: Bing Sun, Ying Wang, Krishna Kota, Yaru Shi, Kepher H. Makambi, Christopher A. Loffredo, Peter G. Shields, Curtis C. Harris, Yun-Ling Zheng. Autosome instability and loss of chromosome Y in blood lymphocytes predict lung cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4157. doi:10.1158/1538-7445.AM2014-4157

Fetal Irradiation of Rats Induces Persistent Translocations in Mammary Epithelial Cells Similar to the Level after Adult Irradiation, but not in Hematolymphoid Cells

In both humans and mice, fetal exposure to radiation fails to induce a persistent increase in the frequency of chromosome aberrations in blood lymphocytes. Such a low-level response to radiation exposure is counterintuitive in view of the generally accepted belief that a fetus is sensitive to radiation. To determine if this is a general phenomenon, both mammary epithelial cells and spleen cells were studied in rats. Fetuses of 17.5 days postcoitus were irradiated with 2 Gy of gamma rays, and mammary tissues were removed 6-45 weeks later. Subsequently, short-term cultures were established to detect translocations using the two-color FISH method. The results showed that translocation frequencies were not only elevated in rats irradiated as fetuses, but were also almost as high as those in rats that were irradiated as adults (12 weeks old, pregnant mothers or young virgins) and examined 6-45 weeks later. There was no evidence of higher sensitivity in fetal cells with respect to the induction of translocations. In contrast, translocation frequencies in spleen cells were not elevated in adult rats irradiated as fetuses but were increased after irradiation of adults as previously seen in mouse spleen cells and human T lymphocytes. In the case of irradiation of adult rats, the induced translocation frequencies were similar between spleen cells and mammary epithelial cells. If we take translocation frequency as a surrogate marker of potential carcinogenic effect of radiation, the current results suggest that fetal irradiation can induce persistent potential carcinogenic damage in mammary stem/progenitor cells but this does not contribute to the increased risk of cancer since it has been reported that irradiation of fetal rats of the SD strain does not increase the risk of mammary cancers. Possible reasons for this discrepancy are discussed.

Directional genomic hybridization: inversions as a potential biodosimeter for retrospective radiation exposure

Chromosome aberrations in blood lymphocytes provide a useful measure of past exposure to ionizing radiation. Despite the widespread and successful use of the dicentric assay for retrospective biodosimetry, the approach suffers substantial drawbacks, including the fact that dicentrics in circulating blood have a rather short half-life (roughly 1-2 years by most estimates). So-called symmetrical aberrations such as translocations are far more stable in that regard, but their high background frequency, which increases with age, also makes them less than ideal for biodosimetry. We developed a cytogenetic assay for potential use in retrospective biodosimetry that is based on the detection of chromosomal inversions, another symmetrical aberration whose transmissibility (stability) is also ostensibly high. Many of the well-known difficulties associated with inversion detection were circumvented through the use of directional genomic hybridization, a method of molecular cytogenetics that is less labor intensive and better able to detect small chromosomal inversions than other currently available approaches. Here, we report the dose-dependent induction of inversions following exposure to radiations with vastly different ionization densities [i.e., linear energy transfer (LET)]. Our results show a dramatic dose-dependent difference in the yields of inversions induced by low-LET gamma rays, as compared to more damaging high-LET charged particles similar to those encountered in deep space.

Chromosomal damage among medical staff occupationally exposed to volatile anesthetics, antineoplastic drugs, and formaldehyde

Structural chromosomal aberrations in blood lymphocytes represent a biomarker for cellular damage caused by genotoxic carcinogens and are an indicator of increased cancer risk. We evaluated the association between frequencies of total chromosomal aberrations, chromatid- and chromosome-type aberrations, and occupational exposures to volatile anesthetics, antineoplastic agents, and formaldehyde among 601 medical professionals. Chromosomal damage among exposed individuals and unexposed controls was determined by conventional cytogenetic analysis. We used binary logistic regression to evaluate the effects of workplace exposures and major confounders on chromosomal damage. Significantly higher frequencies of total chromosomal, chromatid-type and chromosome-type aberrations were observed among subjects occupationally exposed to volatile anesthetics, antineoplastic agents, and formaldehyde compared to age- and sex-matched controls (P<0.0001). The risk of an increased frequency of chromosomal aberrations was associated with exposure to anesthetics [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 2.7-5.8], cytostatics (OR 2.7, 95% CI 1.9-3.9), and formaldehyde (OR 1.7, 95% CI 1.1-2.7). No other covariate contributed significantly to the model. Chromatid- and chromosome-type aberrations were associated with exposure to anesthetics and cytostatics without any contribution of other variables. Stratified data analysis showed the risk of increased chromosomal aberrations among non-smoking female nurses and physicians exposed to anesthetics, cytostatics and, partially, formaldehyde. Chromatid and chromosome exchanges were significantly higher in the exposed groups than among controls. Our findings indicate that the presence of genotoxic compounds in operating rooms, oncological units, and pathological departments results in a significant increase of chromosomal damage (impair of chromosomal integrity) among medical workers employed in these facilities.

Генетические и цитогенетические предикторы радиочувствительности хромосом человека

We studied association between the frequencies of gamma-induced (1 Gy in vitro) chromosome aberrations in blood lymphocytes and polymorphism of 45 repair candidate genes, detoxification and oxidative stress genes (53 sites) for 99 healthy volunteers. The levels of chromosome-type aberrations correlated with carriage of the minor alleles of the genes OGG1 Ser326Cys, ABCB1 Ile1145 = and NQO1 Pro187Ser (p = 0.0002). We have shown that all the revealed genetic associations were less effective in predicting chromosomal radiosensitivity as compared to the correlations between spontaneous and gamma-induced aberrations (p = 1.0 x 10(-6)). The addition of genetic markers to cytogenetic predictors improved the predictive accuracy for chromosomal radiosensitivity with the multiple correlation coefficient reaching R = 0.58 (p = 3.1 x 10(-8)). Thereby we were able to explain more than 30% of the population variability in chromosomal radiosensitivity.

Polymorphism of repair genes and cytogenetic radiation effects

Frequencies of spontaneous and γ-induced (1 Gy in vitro) chromosome aberrations in blood lymphocytes of 99 healthy volunteers were compared with the results of PCR genotyping for eight repair genes: XRCC1, XPD, ERCC1, APEX1, RAD23B, OGG1, ATM, and Tp53 (in all 11 polymorphic sites). The frequency of spontaneous aberrations of the chromosome type additively increased with the number of copies of minor allele variants 2251G and 862A of the nucleotide excision repair gene XPD (p = 0.025). The frequency of γ-induced chromosome aberrations proved to be elevated for the carriers of the minor allele OGG1 977G (p = 0.011). A significantly elevated level of γ-induced chromosome aberrations was also observed for the carriers of the major alleles XRCC1 G1996 and XRCC1 C580 (p = 0.002).

Chromosome Aberrations in Lymphocytes of Prostate Cancer Patients Treated with IMRT and Carbon Ions

Carbon ions are successfully used in tumour treatment for more than 10 years in Chiba and Hyogo (Japan) and at GSI Darmstadt (Germany). Carbon ions are beneficial for the treatment of deep seated tumours, as they deliver the highest dose at the end of their range, and in addition this dose shows an enhanced radiobiological effectiveness. In a clinical study at GSI and at the Clinical Radiology Heidelberg carbon ion therapy is combined with conventional IMRT to treat prostate cancer patients (intermediate risk). In parallel, a study investigating chromosome aberrations in blood lymphocytes of prostate cancer patients is performed. Chromosome aberrations in blood lymphocytes are widely used in biological dosimetry as they represent a sensitive marker for ionizing radiation. Since they are unavoidably exposed to radiation during tumour treatment, this study makes it possible to investigate the cytogenetic effects of carbon ion irradiation in vivo and to compare with conventional tumour treatment. The results may be helpful regarding biological dosimetry, as only very little is known about the effects of partial body irradiation with heavy ions. In this clinical trial, prostate cancer patients are irradiated with a Carbon ion boost (6x3GyE) followed by IMRT (30x2Gy) or solely with IMRT (38x2Gy). Blood samples are drawn from each patient before, during, at the end of and one year after therapy. Lymphocytes are isolated and cultured according to standard techniques, chromosome spreads are prepared and slides are stained using Fluorescence-Plus-Giemsa staining (FPG) and multiplex fluorescence in situ hybridization (mFISH), respectively. In addition, in vitro irradiation experiments with lymphocytes are performed. The number of aberrations found in lymphocytes of prostate cancer patients increases during therapy course, and decreases slightly during the first year after treatment. There is up to now no significant difference visible between patients treated with combined therapy of carbon ions plus IMRT (n=9) and patients treated solely with IMRT (n=2). In addition, prostate cancer patients treated with a larger irradiation field IMRT were included in the study (n=3). The lymphocytes of these patients showed a significantly higher amount of aberrations during therapy course as well as one year after treatment. At the present status of this study, we can conclude that an important influence of irradiation field size on the induced damage in surrounding tissue exists, but that under the given treatment conditions differences in the radiation quality are not observable at chromosomal level.